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Objective Our objective was to test the hypothesis that in‐hospital respiratory viral infections (RVI) would be significantly lower in a cohort of patients with established bronchopulmonary dysplasia (BPD) exposed to a severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection prevention protocol when compared to historical controls. Study Design On April 1, 2020, we implemented a universal infection prevention protocol to minimize the risk of nosocomial SARS‐CoV‐2 transmission in a dedicated BPD intensive care unit. We performed a retrospective cohort study and included patients with established BPD, as defined by the 2019 Neonatal Research Network criteria, admitted to our center who underwent real‐time polymerase‐chain‐reaction RVI testing between January 1, 2015 and March 31, 2021. We excluded patients readmitted from home. We compared the proportion of positive tests to the number of tests performed and the distribution of viral respiratory pathogens in the pre‐ and post‐SARS‐CoV‐2 eras. Results Among 176 patients included in the study, 663 RVI tests were performed and 172 (26%) tests were positive. The median number of tests performed, measured in tests per patient per month, in the SARS‐CoV‐2 era was not significantly different compared to the pre‐SARS‐CoV‐2 era (0.45 vs. 0.34 tests per patient per month, p = .07). The proportion of positive RVI tests was significantly lower in the SARS‐CoV‐2 era when compared to the pre‐SARS‐CoV‐2 era (0.06 vs. 0.30, p

Background: The association between obesity and colorectal cancer (CRC) risk has been well established. This relationship appears to be more significant in men than in women, which may be attributable to sex hormones. However, controlled animal studies to substantiate these claims and the mechanisms involved are lacking. Materials and Methods: MC38 murine colon adenocarcinoma cells were injected subcutaneously into high-fat diet (HFD) fed male, female and ovariectomized (OVX) female C57BL/6 mice. Results: HFD increased tumor growth (main effect) that was consistent with metabolic perturbations (P < 0.01). HFD OVX mice exhibited the most significant tumor growth compared to HFD male and female mice (p < 0.05) and this was associated with increased subcutaneous adipose tissue (p < 0.05). Further, the subcutaneous adipose tissue depots within HFD OVX mice exhibited more severe macrophage associated inflammation compared to female (P < 0.01), but not male mice. Conditioned media from subcutaneous adipose tissue of HFD OVX contained higher IGF-1 levels compared to male (P < 0.01), but not female mice. Finally, HFD OVX mice had increased M2-like gene expression in their tumor-associated macrophages (TAMs) compared to female mice (P < 0.01). Conclusions: This work provides evidences suggesting adiposity, adipose specific IGF-1, macrophage associated adipose inflammation, and TAMs as potential mechanisms driving obesity-enhanced CRC in females lacking ovarian hormones.

Lifestyle interventions may reduce inflammation and lower breast cancer (BrCa) risk. This randomized trial assessed the impact of the Sistas Inspiring Sistas Through Activity and Support (SISTAS) study on plasma C-reactive protein (CRP), interleukin-6 (IL-6) and Dietary Inflammatory Index (DII). This unblinded, dietary and physical activity trial was implemented in 337 obese (body mass index [BMI] ≥30 kg/m(2)) African American (AA) women recruited between 2011 and 2015 in South Carolina through a community-based participatory approach with measurements at baseline, 3 months, and 12 months. Participants were randomized into either intervention (n=176) or wait-list control group (n=161). Linear mixed-effect models were used for analyses of CRP and IL-6. Baseline CRP was significantly higher in those with greater obesity, body fat percentage, and waist circumference (all p-values

Maternal diets can have dramatic effects on the physiology, metabolism, and behaviour of offspring that persist into adulthood. However, the effects of maternal sucrose consumption on offspring remain unclear. Here, female rats were fed either a sucrose diet with a human-relevant level of sucrose (25% of kcal) or a macronutrient-matched, isocaloric control diet before, during, and after pregnancy. After weaning, all offspring were fed a standard low-sucrose rodent chow. We measured indicators of metabolism (weight, adipose, glucose tolerance, and liver lipids) during development and adulthood (16–24 weeks). We also measured food preference and motivation for sugar rewards in adulthood. Finally, in brain regions regulating these behaviours, we measured steroids and transcripts for steroidogenic enzymes, steroid receptors, and dopamine receptors. In male offspring, maternal sucrose intake decreased body mass and visceral adipose tissue, increased preference for high-sucrose and high-fat diets, increased motivation for sugar rewards, and decreased mRNA levels of Cyp17a1 (an androgenic enzyme) in the nucleus accumbens. In female offspring, maternal sucrose intake increased basal corticosterone levels. These data demonstrate the enduring, diverse, and sex-specific effects of maternal sucrose consumption on offspring phenotype.

Objective Our objective was to test the hypothesis that in-hospital respiratory viral infections (RVI) would be significantly lower in a cohort of patients with established bronchopulmonary dysplasia in the SARS-CoV-2 era when compared to historical controls. Study Design On April 1, 2020, we implemented a universal infection prevention bundle to minimize the risk of nosocomial SARS-CoV-2 transmission in a dedicated BPD intensive care unit. We performed a retrospective cohort study and included patients with established BPD, as defined by the 2019 Neonatal Research Network criteria, admitted to our center who underwent real-time polymerase-chain-reaction RVI testing between January 1, 2015 and March 31, 2021. We excluded patients re-admitted from home. We compared to number of tests performed, the proportion of positive tests, and the distribution of viral respiratory pathogens in the pre- and post-SARS-CoV-2 eras. Results Among 176 patients included in the sudy, 663 RVI tests were performed and 172 (26%) tests were positive. The median number of tests performed, measured in tests per patient per month, in the SARS-CoV-2 era was not significantly different compared to the pre-SARS-CoV-2 era (0.45 vs 0.34 tests per patient per month, P = 0.07). The proportion of positive RVI tests was significantly lower in the SARS-CoV-2 era when compared to the pre-SARS-CoV-2 era (0.06 vs 0.30, P

Our previous studies demonstrated that the natural compound emodin blocks the tumor-promoting feedforward interactions between cancer cells and macrophages, and thus ameliorates the immunosuppressive state of the tumor microenvironment. Since tumor-associated macrophages (TAMs) also affect epithelial mesenchymal-transition (EMT) and cancer stem cell (CSC) formation, here we aimed to test if emodin as a neoadjuvant therapy halts breast cancer metastasis by attenuating TAM-induced EMT and CSC formation of breast cancer cells. Methods: Bioinformatical analysis was performed to examine the correlation between macrophage abundance and EMT/CSC markers in human breast tumors. Cell culture and co-culture studies were performed to test if emodin suppresses TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells, and if it inhibits breast cancer cell migration and invasion. Using mouse models, we tested if short-term administration of emodin before surgical removal of breast tumors halts breast cancer post-surgery metastatic recurrence in the lungs. The effects of emodin on TGF-β1 signaling pathways in breast cancer cells were examined by western blots and immunofluorescent imaging. Results: Macrophage abundance positively correlates with EMT and CSC markers in human breast tumors. Emodin suppressed TGF-β1 production in breast cancer cells and macrophages and attenuated TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells. Short-term administration of emodin before surgery halted breast cancer post-surgery metastatic recurrence in the lungs by reducing tumor-promoting macrophages and suppressing EMT and CSC formation in the primary tumors. Mechanistic studies revealed that emodin inhibited both canonical and noncanonical TGF-β1 signaling pathways in breast cancer cells and suppressed transcription factors key to EMT and CSC. Conclusion: Natural compound emodin suppresses EMT and CSC formation of breast cancer cells by blocking TGF-β1-mediated crosstalk between TAMs and breast cancer cells. Our study provides evidence suggesting that emodin harbors the potential for clinical development as a new effective and safe agent to halt metastatic recurrence of breast cancer.

Over the past decade, the search for dietary factors on which to base cancer prevention guidelines has led to the rapid expansion of the field of dietary patterns and cancer. Multiple systematic reviews and meta-analyses have reported epidemiological associations between specific cancer types and both data-driven dietary patterns determined by empirical analyses and investigator-defined dietary indexes based on a predetermined set of dietary components. New developments, such as the use of metabolomics to identify objective biomarkers of dietary patterns and novel statistical techniques, could provide further insights into the links between diet and cancer risk. Although animal models of dietary patterns are limited, progress in this area could identify the potential mechanisms underlying the disease-specific associations observed in epidemiological studies. In this Review, we summarize the current state of the field, provide a critical appraisal of new developments and identify priority areas for future research. An underlying theme that emerges is that the effectiveness of different dietary pattern recommendations in reducing risk could depend on the type of cancer or on other risk factors such as family history, sex, age and other lifestyle factors or comorbidities as well as on metabolomic signatures or gut microbiota profiles.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that (1) mimic the human manifestation of NAFLD and (2) have a longer progression time to allow for the design of superior treatments. AIM To characterize a model of prolonged high-fat diet (HFD) feeding for investigation of the long-term progression of NAFLD. METHODS In this study, we utilized prolonged HFD feeding to examine NAFLD features in C57BL/6 male mice. We fed mice with a HFD (60% fat, 20% protein, and 20% carbohydrate) for 80 wk to promote obesity (Old-HFD group, n = 18). A low-fat diet (LFD) (14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice (Old-LFD group, n = 15). An additional group of mice was maintained on the LFD (Young-LFD, n = 20) for a shorter duration (6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments. RESULTS Prolonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia, Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice. CONCLUSION Overall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.

Depletion of macrophages is thought to be a therapeutic option for obesity-induced inflammation and metabolic dysfunction. However, whether the therapeutic effect is a direct result of reduced macrophage-derived inflammation or secondary to decreases in fat mass is controversial, as macrophage depletion has been shown to disrupt energy homeostasis. This study was designed to determine if macrophage depletion via clodronate-liposome (CLD) treatment could serve as an effective intervention to reduce obesity-driven inflammatory and metabolic impairments independent of changes in energy intake. After 16 wk on a high-fat diet (HFD) or the AIN-76A control (low-fat) diet (LFD) ( n = 30/diet treatment), male C57BL/6J mice were assigned to a CLD- or PBS-liposome treatment ( n = 15/group) for 4 wk. Liposomes were administered biweekly via intraperitoneal injections (8 administrations in total). PBS-liposome-treated groups were pair-fed to their CLD-treated dietary counterparts. Metabolic function was assessed before and after liposome treatment. Adipose tissue, as well as the liver, was investigated for macrophage infiltration and the presence of inflammatory mediators. Additionally, a complete blood count was performed. CLD treatment reduced energy intake. When controlling for energy intake, CLD treatment was unable to regress metabolic dysfunction or nonalcoholic fatty liver disease and impaired adipose tissue insulin action. Moreover, repeated CLD treatment induced neutrophilia and anemia, increased adipose tissue mRNA expression of the proinflammatory cytokines IL-6 and IL-1β, and augmented circulating IL-6 and monocyte chemoattractant protein-1 concentrations ( P < 0.05). This study suggests that repeated intraperitoneal administration of CLD to deplete macrophages attenuates obesity by limiting energy intake. Moreover, after controlling for the benefits of weight loss, the accompanying detrimental side effects limit regular CLD treatment as an effective therapeutic strategy.

Intestinal mucositis remains one of the most debilitating side effects related to chemotherapy. The onset and persistence of mucositis is an intricate physiological process involving cross-communication between the specific chemotherapeutic drug, the immune system, and gut microbes that results in a loss of mucosal integrity leading to gut-barrier dysfunction. Intestinal mucositis has a severe impact on a patient’s quality of life and negatively influences the outcome of treatment. Most importantly, intestinal mucositis is a major contributor to the decreased survival rates and early onset of death associated with certain chemotherapy treatments. Understanding the pathophysiology and symptomology of intestinal mucositis is important in reducing the negative consequences of this condition. Prophylaxis, early diagnosis, and proper symptom management are essential to improved survival outcomes in patients with cancer. This review focuses on the pathobiology of intestinal mucositis that accompanies chemotherapy treatments. In addition, we will discuss the therapeutic potential of select strategies that have shown promise in mitigating chemotherapies’ off-target effects without hampering their anticancer efficacy. NEW & NOTEWORTHY Intestinal mucositis, or damage to the intestinal mucosa, is a common side effect of chemotherapy. In this review, we describe the pathobiology of intestinal mucositis that is associated with chemotherapy treatments. In addition, we discuss the efficacy of several potential therapeutic strategies that have shown some potential in alleviating chemotherapies’ off-target effects.

Weight fluctuations are common among individuals with obesity and are associated with increased morbidity. We examined adipose tissue immune and inflammatory markers in mice following weight loss and partial weight regain. Male C57BL/6 mice were randomized into four groups (n = 8–10/group): low-fat diet for 32 wk (LFD), high-fat diet for 32 wk (HFD), LFD for 28 wk and then changed to a HFD for 4 wk (LFD→H), and HFD for 21 wk and then changed to LFD for 7 wk and then changed to HFD for 4 wk (HFD→L→H). LFD→H and HFD→L→H mice did not differ in body weight, fat mass, or fat percentage; however, these parameters were greater than in LFD (P < 0.05) but lower than in HFD (P < 0.05). HFD→L→H mice had smaller adipocytes than HFD and LFD→H (P < 0.05) but not LFD mice. Expressions of CD11c and CD8a genes were elevated in epididymal fat of HFD→L→H compared with LFD→H and LFD (P < 0.05)mice. However, CD11c was lower in HFD→L→H than in HFD mice (P < 0.05), but there was no difference in CD8a between these groups. TNFα and IFNγ expressions were increased in HFD→L→H compared with LFD and LFD→H mice (P < 0.05), although HFD→L→H had lower expression of these cytokines than HFD (P < 0.05). IL-1β was greater in HFD→L→H compared with LFD (P < 0.05) but was not different from LFD→H or HFD mice. Monocyte chemoattractant protein-1 was lower (P < 0.05) in HFD→L→H than in LFD→H. These data reinforce the importance of maintaining a body weight in the range that is recommended for optimal health to reduce immune and inflammatory perturbations associated with obesity. NEW & NOTEWORTHY We examined the immune and inflammatory status of adipose tissue in mice after they underwent weight loss followed by partial weight regain. We show an increase in selected immune cells and inflammatory mediators, in high-fat diet-fed mice that had prior exposure to a high-fat diet. Although weight fluctuations appear to exacerbate immune cell abundance and inflammation in adipose tissue, severity is less than in mice that were exposed to sustained high-fat diet feedings.

BackgroundTumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development.MethodsMicroarrays were used to analyze the gene expression profile of macrophages (MΦs) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects MΦ gene expression and function. Mouse studies were carried out to investigate the impact of MΦ TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes.ResultsTAM-mimic MΦs display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor γ (PPARγ) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1α mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1β, IL-6 and prostaglandin E2. MΦ-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPARγ are positive prognostic markers, while HIF-1α is a negative prognostic marker of breast cancer.ConclusionsOur study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.

Progressive weight loss combined with skeletal muscle atrophy, termed cachexia, is a common comorbidity associated with cancer that results in adverse consequences for the patient related to decreased chemotherapy responsiveness and increased mortality. Cachexia's complexity has provided a barrier for developing successful therapies to prevent or treat the condition, since a large number of systemic disruptions that can regulate muscle mass are often present. Furthermore, considerable effort has focused on investigating how tumor derived factors and inflammatory mediators directly signal skeletal muscle to disrupt protein turnover regulation. Currently, there is developing appreciation for understanding how cancer alters skeletal muscle's complex microenvironment and the tightly regulated interactions between multiple cell types. Skeletal muscle microenvironment interactions have established functions in muscle response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise. This review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting. Emphasis is placed on the regulatory network that integrates physiological responses between immune cells with other muscle cell types including satellite cells, fibroblast cells, and endothelial cells to regulate myofiber size and plasticity. The overall goal of this review is to provide an understanding of how different cell types that constitute the muscle microenvironment and their signaling mediators contribute to cancer and chemotherapy-induced muscle wasting.

Staphylococcal enterotoxin B (SEB) is a potent superantigen produced by Staphylococcus aureus that triggers a strong immune response, characterized by cytokine storm, multi‐organ failure, and often death. When inhaled, SEB can cause acute lung injury (ALI) and respiratory failure. In this study, we investigated the effect of resveratrol (RES), a phytoallexin, on SEB‐driven ALI and mortality in mice. We used a dual‐exposure model of SEB in C3H/HeJ mice, which caused 100% mortality within the first 5 days of exposure, and treatment with RES resulted in 100% survival of these mice up to 10 days post‐SEB exposure. RES reduced the inflammatory cytokines in the serum and lungs, as well as T cell infiltration into the lungs caused by SEB. Treatment with RES also caused increased production of transforming growth factor‐beta (TGF‐β) in the blood and lungs. RES altered the miRNA profile in the immune cells isolated from the lungs. Of these, miR‐193a was strongly induced by SEB and was down‐regulated by RES treatment. Furthermore, transfection studies and pathway analyses revealed that miR‐193a targeted several molecules involved in TGF‐β signalling (TGFβ2, TGFβR3) and activation of apoptotic pathways death receptor‐6 (DR6). Together, our studies suggest that RES can effectively neutralize SEB‐mediated lung injury and mortality through potential regulation of miRNA that promote anti‐inflammatory activities.

We examined the role of macrophages in inflammation associated with colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we also sought to examine the interaction between macrophages and gut microbiota. To induce CRC, male C57BL/6 mice ( n = 32) received a single injection of azoxymethane (AOM), followed by three cycles of dextran sodium sulfate (DSS)-supplemented water in weeks 1, 4, and 7. Prior to the final DSS cycle ( week 7) and twice weekly until euthanasia, mice ( n = 16/group) received either 200 μl ip of clodronate-filled liposomes (CLD) or phosphate-buffered saline (PBS) encapsulated liposomes to deplete macrophages. Colon tissue was analyzed for polyp burden, macrophage markers, transcription factors, and inflammatory mediators. Stool samples were collected, and DNA was isolated and subsequently sequenced for 16S rRNA. Clodronate liposomes decreased tumor number by ∼36% and specifically large (≥1 mm) tumors by ∼36% ( P < 0.05). This was consistent with a decrease in gene expression of EMR1 in the colon tissue and polyp tissue as well as expression of select markers associated with M1 (IL-6) and M2 macrophages (IL-13, IL-10, TGFβ, CCL17) in the colon tissue ( P < 0.05). Similarly, there was a decrease in STAT3 and p38 MAPK and ERK signaling in colon tissue. Clodronate liposomes increased the relative abundance of the Firmicutes phylum ( P < 0.05) and specifically Lactobacillaceae and Clostridiaceae families, which have been associated with reduced CRC risk. Overall, these data support the development of therapeutic strategies to target macrophages in CRC and provide support for further evaluation of immune-microbiota interactions in CRC. NEW & NOTEWORTHY We found that macrophage depletion during late-stage tumorigenesis is effective at reducing tumor growth. This was associated with a decrease in macrophage markers and chemokines in the colon tissue and a decrease in transcription factors that are linked to colorectal cancer. The macrophage-depleted group was found to have an increased abundance of Firmicutes, a phylum with documented anti-tumorigenic effects. Overall, these data support the development of therapeutic strategies to target macrophages in colorectal cancer.

Obesity is characterized by chronic low-grade, systemic inflammation, altered gut microbiota, and gut barrier disruption. Additionally, obesity is associated with increased activity of endocannabinoid system (eCB). However, the clear connection between gut microbiota and the eCB system in the regulation of energy homeostasis and adipose tissue inflammation and metabolism, remains to be established. We investigated the effect of treatment of mice with a cannabinoid receptor 1 (CB1) antagonist on Diet-Induced Obesity (DIO), specifically whether such a treatment that blocks endocannabinoid activity can induce changes in gut microbiota and anti-inflammatory state in adipose tissue. Blockade of CB1 attenuated DIO, inflammatory cytokines and trafficking of M1 macrophages into adipose tissue. Decreased inflammatory tone was associated with a lower intestinal permeability and decreased metabolic endotoxemia as evidenced by reduced plasma LPS level, and improved hyperglycemia and insulin resistance. 16S rRNA metagenomics sequencing revealed that CB1 blockade dramatically increased relative abundance of Akkermansia muciniphila and decreased Lanchnospiraceae and Erysipelotrichaceae in the gut. Together, the current study suggests that blocking of CB1 ameliorates Diet-Induced Obesity and metabolic disorder by modulating macrophage inflammatory mediators, and that this effect is associated with alterations in gut microbiota and their metabolites.

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The ApcMin/+mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female ApcMin/+mouse. Our study of ovarian reproductive function in female ApcMin/+mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female ApcMin/+mice.

Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as "common variable immunodeficiency" (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19-/- mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19-/- mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19-/- mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19-/- mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19-/- mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19-/- mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.

Arthrogryposis multiplex congenita involves stiff contracture of joints and weak atrophic muscles presenting at birth. The two most common forms are amyoplasia and distal arthrogryposis. Amyoplasia affects all 4 extremities: internally rotated shoulders, extended fixed elbows, flexed fixed wrists, extended fixed knees, clubfeet, and decreased muscle volume. Distal arthrogryposis is a group of syndromes with a genetic basis. The distal joints are contracted. Clubfeet and congenital vertical talus are the most common foot deformities. A 10-year-old boy presented with distal arthrogryposis with bilateral congenital tali. He reported having deformed and painful feet and difficulty wearing shoes. His rocker-bottom foot deformities caused him to walk with a heel to heel gait. He also had stiff extended knees. His previous foot surgeries included failed open reduction and pin fixation of the talonavicular joints with Achilles tendon lengthening and capsulotomies. The boy underwent bilateral talectomies and releases of contracted joint capsules and lengthening of multiple extrinsic tendons through separate incisions. The talectomy of each foot was performed via a novel medial surgical approach. At 2-year follow-up, he had normal-appearing plantar grade feet. He had a painless gait, could ambulate independently, and was considered to have an excellent result. This is the first detailed report of performing a talectomy via a medial approach for bilateral congenital tali in a patient with arthrogryposis multiplex congenita. [ Orthopedics . 2020; 43(6):e623–e626.]

// Aditi A. Narsale 1, * , Melissa J. Puppa 1, * , Justin P. Hardee 1, * , Brandon N. VanderVeen 1 , Reilly T. Enos 2 , E. Angela Murphy 2 , James A. Carson 1, 3 1 Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA 2 Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, USA 3 Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina, USA * These authors have contributed equally to this work Correspondence to: James A. Carson, email: carsonj@mailbox.sc.edu Keywords: hepatomegaly, muscle atrophy, protein turnover, inflammation, metabolism Received: March 04, 2016 Accepted: July 09, 2016 Published: July 19, 2016 ABSTRACT Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to Apc Min/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age Apc Min/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control Apc Min/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

Introduction The aim of this study was to assess the total frequency of self-treated hypoglycemia in type 2 diabetes mellitus patients using regimens including basal insulin analogs, and to describe the psychological impact and behavioral response to these events from the perspective of patients and prescribers (i.e., hospital specialists and primary care physicians). Methods The global attitude of patients and physicians 2 (GAPP2) survey was an online multinational, cross-sectional survey of patients with type 2 diabetes mellitus treated with basal insulin analogs, with or without bolus insulin. Prescribers directly involved in the care of these patients were also surveyed. Here, we report the results of the second wave of the GAPP2 survey, in which the primary variable of interest was self-treated hypoglycemia. Results A total of 855 patients and 1003 prescribers, from 7 countries, completed the survey. Overall, 28% of patients had experienced self-treated hypoglycemia during the previous 30 days, with two-thirds of events occurring during the day and one-third of events occurring nocturnally. Prescribers reported discussing events with 55% of patients over this period. Patients worried about self-treated hypoglycemia in a range of situations, and prescribers under-estimated this worry. Many patients who had experienced self-treated hypoglycemia in the last 30 days reported missing (19%), mistiming (7%), or reducing (7%) their basal insulin dose as a result. Conclusion Self-treated hypoglycemia was relatively common in patients using basal insulin analogs, with or without bolus insulin. Whilst the frequency of hypoglycemia was greater during the daytime than at night, patients worried more about nocturnal events and this level of worry was under-estimated by physicians. Additional advice and support may be needed for both patients and prescribers, to reduce the frequency and impact of self-treated hypoglycemia. Funding Novo Nordisk.

e21737 Background: Lung cancer is the leading cause of cancer death in Australia with 13,000 new cases per year. Although targeted therapy and immunotherapy have drastically changed the treatment landscape, the majority of patients will receive platinum-based chemotherapy for which the response rate is approximately 30% (Reck et al, 2016). An immunohistochemistry-based, predictive biomarker would be beneficial for patients and help avoid toxicity for patients unlikely to respond. Marini et al (2018) identified 3 biomarkers associated with in-vitro platinum resistance – activin A, growth differentiation factor-11 and transforming growth factor-b – which were investigated in a real-world retrospective cohort to determine their relation to objective radiological response and overall survival. Methods: We identified 101 patients with advanced non-small cell lung cancer who received platinum chemotherapy at 2 cancer centres between 2014-2015. Archival formalin-fixed paraffin embedded tissue samples were stained with activin A. Slides were manually scored by 2 independent clinicians using the multiplicative quickscore method (Detre et al, 1995). Kaplan Meier analysis for overall survival, a Cox-proportional hazards model for confounding variables and a chi-square analysis was performed to analyse the relationship between high immunohistochemistry scores (greater or less than 6) and radiological response. Results: We performed statistical analysis around the median cytoplasmic score (6). The overall median survival was 15.3 months. No significant difference in survival was detected between the two populations (p value = 0.97). The immunohistochemistry score was also not associated with rates of partial response (p value = 0.98) or progressive disease (p value 0.22). Conclusions: Despite an association with lower progression-free survival in a retrospective cohort in a previous study, high expression of activin does not appear to be a useful biomarker for platinum response in the setting of non-small cell lung cancer. Further research into associated antibodies including GDF-11 and TGF-b is in progress.

PURPOSE: Dietary factors may influence colorectal cancer (CRC) survival through effects on inflammation. We examined the association between post-CRC diagnosis inflammatory potential of diet and all-cause and cancer-specific mortality in the Women’s Health Initiative. METHODS: The study included 463 postmenopausal women who developed CRC during follow-up and completed a food frequency questionnaire (FFQ), on average 1.7 years after diagnosis. Women were followed from CRC diagnosis until death, censoring, or the end of follow up in October 2014. Energy-adjusted dietary inflammatory index (E-DII)® scores were calculated from the FFQ and dietary supplement inventory. Cox proportional hazards models were fitted to estimate multivariable-adjusted HRs and 95% confidence intervals (CI) for all-cause, total cancer, and CRC-specific mortality with the most pro-inflammatory E-DII scores (tertile 3) as referent. RESULTS: After a median 11.6 years of follow-up, 162 deaths occurred, including 77 from CRC. Lowest tertile (i.e., most anti-inflammatory) E-DII scores from diet plus supplements were associated with significantly lower all-cause mortality (HR(T1vsT3)=0.49; 95% CI=0.31–0.79) compared to the most pro-inflammatory E-DII tertile. Modest associations with total cancer mortality or CRC-specific mortality were observed, though 95%CIs included 1. CONCLUSIONS: Consuming a dietary pattern and supplements with more anti-inflammatory potential after CRC diagnosis may improve overall survival among postmenopausal women.

This chapter presents some findings and critical discussion of narrative inquiry research which sought to explore how possible selves are shaped in Master’s level healthcare students with dyslexia. The findings communicated here recount and discuss a significant narrative plot relating to the contextual implications of living with dyslexia and the highly significant roles played by the research participants’ families. Narratives are presented here as an Act and Scene, inviting the reader to interact directly with the narratives of the participants and consider the ontological and epistemological positions enabled by the possible selves’ concept when applied within educational research. The chapter considers the importance of families on possible selves, family dynamics and resources and the role of agency which are found here to be highly important in the shaping of possible selves. A significant contribution provided within this chapter to the wider possible selves’ literature relates to the finding that possible selves are shown here to be shared or imagined by parents (parental possible selves) and inherited within families.

Introduction: Recruiting racial, ethnic, and other underserved minorities into conven­tional clinic-based and other trials is known to be challenging. The Sistas Inspiring Sistas Through Activity and Support (SISTAS) Pro­gram was a one-year randomized controlled trial (RCT) to promote physical activity and healthy eating among AA women in SC to reduce inflammatory biomarkers, which are linked to increased breast cancer (BrCa) risk and mortality. This study describes the development, recruitment, and imple­mentation of the SISTAS clinical trial and provides baseline characteristics of the study participants.Methods: SISTAS was developed using community-based participatory research (CBPR) approaches. At baseline, study participants completed assessments and underwent clinical measurements and blood draws to measure C-reactive protein (CRP) and interleukin-6 (IL-6). Participants randomized to the intervention received 12 weekly classes followed by nine monthly booster sessions. Post-intervention mea­surements were assessed at 12-week and 12-month follow-ups.Results: We recruited a total of 337 women who tended to: be middle-aged (mean age 48.2 years); have some college education; be employed full-time; have Medicare as their primary insurance; be non-smokers; and perceive their personal health as good. On average, the women were pre-hyper­tensive at baseline (mean systolic blood pressure = 133.9 mm Hg; mean diastolic blood pressure = 84.0 mm Hg) and mor­bidly obese (mean BMI >40.0 kg/m2); the mean fat mass and fat-free mass among participants were 106.4 lb and 121.0 lb, respectively.Conclusion: The SISTAS RCT addresses some of the gaps in the literature with respect to CBPR interventions target­ing AA women, such as implementing diet and physical activity in CBPR-based studies to decrease BrCa risk.Ethn Dis. 2018;28(2):75-84; doi:10.18865/ ed.28.2.75.

It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise in obesity and related health ailments. However, no tightly controlled studies using high-fat diets differing in the n-6:n-3 have tested this hypothesis. The aim of the study was to determine the role that the dietary n-6:n-3 plays in non-alcoholic fatty-liver disease (NAFLD) and colitis development. We hypothesized that reducing the dietary n-6:n-3 would hinder the development of NAFLD and colitis. Male C57BL/6 J mice were fed high-fat diets, differing in the n-6:n-3 (1:1, 5:1, 10:1, 20:1), for 20 weeks. Gas chromatography-mass spectrometry was used to analyze the hepatic phospholipid arachidonic acid (AA):eicosapentaenoic acid and AA:docosahexaenoic acid. Hepatic metabolism, inflammatory signaling, macrophage polarization, gene expression of inflammatory mediators, oxidative and endoplasmic reticulum stress, and oxidative capacity were assessed as well as colonic inflammatory signaling, and gene expression of inflammatory mediators and tight-junction proteins. Although reducing the dietary n-6:n-3 lowered the hepatic phospholipid AA:eicosapentaenoic acid and AA:docosahexaenoic acid in a dose-dependent manner and mildly influenced inflammatory signaling, it did not significantly attenuate NAFLD development. Furthermore, the onset of NAFLD was not paired to colitis development or changes in tight-junction protein gene expression. In conclusion, reducing the dietary n-6:n-3 did not attenuate NAFLD progression; nor is it likely that colitis, or gut permeability, plays a role in NAFLD initiation in this model.

Aims Hypoglycemia constitutes a significant barrier to achieving glycemic control with insulin in both type 1 and type 2 diabetes. Historically, it has been difficult to accurately verify the rates of hypoglycemia within a clinical setting and there is a need for high-quality, real-world data to ascertain the true rates of hypoglycemia in clinical practice. The global Hypoglycemia Assessment Tool (HAT) study was designed to assess the global incidence of hypoglycemia in patients with insulin-treated diabetes, and the results have indicated that the overall incidence of hypoglycemia is high, with large variations between geographical regions. Methods The International Operations HAT (IO HAT) study retrospectively and prospectively assessed the incidence of hypoglycemia in patients with insulin-treated diabetes in Bangladesh, Colombia, Egypt, Indonesia, Philippines, Singapore, South Africa, Turkey, and United Arab Emirates. Results During the prospective period, hypoglycemic events were reported by 97.4% of patients with type 1 diabetes and 95.3% of those with type 2 diabetes, with an estimated rate of 6.86 events per patient per month (PPPM) for patients with type 1 diabetes and 2.37 events PPPM for patients with type 2 diabetes. Conclusions These results represent the first patient-reported dataset on hypoglycemia in the participating countries and confirm that hypoglycemia is under-reported and more widespread than previously believed. Although the incidence of hypoglycemia was variable among patients on different treatment regimens, there were substantial impacts on both productivity and healthcare utilization following an episode of hypoglycemia. This trial is registered at clinicaltrials.gov: NCT02306681.

Background Previous research has found that African American (AA) vegetarians/vegans have a significantly lower body mass index and risk of hypertension compared to omnivores. Objectives The Nutritious Eating with Soul (NEW Soul) study partnered with local soul food restaurants/chefs to deliver two behavioral nutrition interventions to AA adults. NEW Soul examines the impact of two different culturally tailored diets (vegan and omnivorous low-fat) on changes in risk factors for cardiovascular disease (CVD). Methods AA adults with overweight or obesity are recruited from the community in the Midlands of South Carolina. Eligible participants are randomized to follow one of two different culturally-adapted, soul food diets: a vegan diet emphasizing minimally-processed whole foods from plants or a low-fat omnivorous diet. Participants attend weekly group classes for the first six months, bi-weekly for the next six months, and monthly meetings for the last year. In addition to face-to-face content, participants also have access to private Facebook groups for their diet, podcasts, and online newsletters starting at six months. Primary outcomes include changes in body weight and CVD risk factors (lipids, blood pressure, glucose, and insulin) at 12 months. Secondary outcomes include changes in dietary intake. Participants complete assessments at baseline and at months 6, 12, and 24. Conclusions The NEW Soul study is an innovative intervention aimed at improving dietary intake while maintaining traditional AA cultural food choices. Primary outcomes are expected by 2021.

Many observational epidemiologic studies suggest an association between exercise and colon cancer risk. The mechanisms contributing to a preventative effect of exercise on colon cancer are complex and multifaceted. Altered immune system function is one possible mechanism that has been largely unexplored. Therefore, the purpose of this study was to examine the effects of exercise on markers associated with macrophages and select T cell populations in a mouse model of intestinal tumorigenesis and to relate this to polyp characteristics. Male Apc(Min/+) mice were randomly assigned to either sedentary (Sed) or exercise (Ex) treatment (n=6-9/group). The exercise treatment consisted of treadmill running for 1 h/day and 6 days a week at 15 m/min from 4 until 16 weeks of age. Intestinal polyps were counted and categorized by size. Mucosal tissue was analyzed for mRNA expression of overall macrophages (F4/80), for genes associated with M1 (IL-12, IL-23 and Nos2) and M2 (CD206, IL-10, IL-4, CCL17, CCL22 and Arg-1) macrophages and the macrophage chemoattractants MCP-1, fetuin A and CXCL14. Markers for cytotoxic T cells (CTLs) and regulatory T cells were also examined by measuring mRNA expression of CD8 and Foxp3, respectively. While there was no significant difference in overall polyp number between the groups (Sed, 23.3±4.3; and Ex, 16.5±4.3), Ex did have a reduction in the number of large polyps (Sed, 6.1±1.1; and Ex, 3.0±0.6) (P

Purpose. While fatigue is the most commonly reported symptom of chemotherapy, there are currently no effective treatments for chemotherapy-induced fatigue (CIF). We used a mouse model to examine the benefits of quercetin on CIF as measured by voluntary wheel running activity and sought to determine whether quercetin may be associated with a decrease in inflammation and/or anemia. Methods. Mice were assigned to 1 of 4 groups: placebo-vehicle (Plac-PBS), placebo-5-fluorouracil (Plac-5FU), quercetin-vehicle (Quer-PBS), or quercetin-5-fluorouracil (Quer-5FU). All mice were given a daily injection of either 60 mg/kg of 5-FU or phosphate buffered saline (PBS) for 5 days. Quercetin (0.02%) treatment was administered in the food 3 days prior to 5-FU administration and for the duration of the experiment (ie, days −2 to 14). A second group of mice was sacrificed at 5 and 14 days post initial injection for assessment of monocyte chemoattractant protein-1 (MCP-1) and anemia. Results. Voluntary wheel running was reduced in both the Plac-5FU and Quer-5FU groups following 5-FU injection ( P < .05). However, the Quer-5FU group recovered to baseline levels by approximately day 7, whereas the Plac-5FU group remained suppressed. MCP-1 was significantly elevated at 14 days in Plac-5FU ( P < .001), but no changes were seen with Quer-5FU. Treatment with 5-FU resulted in anemia at both 5 days and 14 days; however, quercetin blocked this effect at 14 days ( P < .001). Conclusion. These results demonstrate the beneficial effect of quercetin on improving recovery of voluntary physical activity following 5-FU treatment, which may be linked to a decrease in inflammation and anemia.

Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a major modulator in the progression of mammary tumorigenesis, largely due to its ability to recruit macrophages to the tumor microenvironment. Macrophages are key mediators in the connection between inflammation and cancer progression and have been shown to play an important role in tumorigenesis. Thus, MCP-1 may be a potential therapeutic target in inflammatory and difficult-to-treat cancers such as triple negative breast cancer (TNBC). We examined the effect of MCP-1 depletion on mammary tumorigenesis in a model of TNBC. Tumor measurements were conducted weekly (until 22 weeks of age) and at sacrifice (23 weeks of age) in female C3(1)/SV40Tag and C3(1)/SV40Tag MCP-1 deficient mice to determine tumor numbers and tumorvolumes. Histopathological scoring was performed at 12 weeks of age and 23 weeks of age. Gene expression of macrophage markers and inflammatory mediators were measured in the mammary gland and tumor microenvironment at sacrifice. As expected, MCP-1 depletion resulted in decreased tumorigenesis, indicated by reduced primary tumor volume and multiplicity, and a delay in tumor progression represented by histopathological scoring (12 weeks of age). Deficiency in MCP-1 significantly downregulated expression of macrophage markers in the mammary gland (Mertk and CD64) and the tumor microenvironment (CD64), and also reduced expression of inflammatory cytokines in the mammary gland (TNFα and IL-1β) and the tumor microenvironment (IL-6). These data support the hypothesis that MCP-1 expression contributes to increased tumorigenesis in a model of TNBC via recruitment of macrophages and subsequent increase in inflammatory mediators.

Obesity presents a significant public health concern given its association with increased cancer incidence, unfavorable prognosis, and metastasis. However, there is very little literature on the effects of weight loss, following obesity, on risk for colon cancer or liver cancer. Therefore, we sought to study whether intentional weight loss through diet manipulation was capable of mitigating colon and liver cancer in mice. We fed mice with a high-fat diet (HFD) comprised of 47% carbohydrates, 40% fat, and 13% protein for 20 wk to mimic human obesity. Subsequently, azoxymethane (AOM) was used to promote colon and liver carcinogenesis. A subset of obese mice was then switched to a low-fat diet (LFD) containing 67.5% carbohydrate, 12.2% fat, and 20% protein to promote intentional weight loss. Body weight loss and excess fat reduction did not protect mice from colon cancer progression and liver dysplastic lesion in the AOM-chemical-cancer model even though these mice had improved blood glucose and leptin levels. Intentional weight loss in AOM-treated mice actually produced histological changes that resemble dysplastic alterations in the liver and presented a higher percentage of F4/80+CD206+ macrophages and activated T cells (CD4+CD69+) in the spleen and lymph nodes, respectively. In addition, the liver of AOM-treated mice exposed to a HFD during the entire period of the experiment exhibited a marked increase in proliferation and pNF-κB activation. Altogether, these data suggest that intentional weight loss following chemical-induced carcinogenesis does not affect colon tumorigenesis but may in fact negatively impact liver repair mechanisms.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which is thought to result from immune-mediated inflammatory disorders, leads to high morbidity and health care cost. Fatty acid amide hydrolase (FAAH) is an enzyme crucially involved in the modulation of intestinal physiology through anandamide (AEA) and other endocannabinoids. Here we examined the effects of an FAAH inhibitor (FAAH-II), on dextran sodium sulphate (DSS)-induced experimental colitis in mice. Treatments with FAAH-II improved overall clinical scores by reversing weight loss and colitis-associated pathogenesis. The frequencies of activated CD4+ T cells in spleens, mesenteric lymph nodes (MLNs), Peyer's patches (PPs), and colon lamina propiria (LP) were reduced by FAAH inhibition. Similarly, the frequencies of macrophages, neutrophils, natural killer (NK), and NKT cells in the PPs and LP of mice with colitis declined after FAAH blockade, as did concentrations of systemic and colon inflammatory cytokines. Microarray analysis showed that 26 miRNAs from MLNs and 217 from PPs had a 1.5-fold greater difference in expression after FAAH inhibition. Among them, 8 miRNAs were determined by reverse-transcription polymerase chain reaction (RT-PCR) analysis to have anti-inflammatory properties. Pathway analysis demonstrated that differentially regulated miRNAs target mRNA associated with inflammation. Thus, FAAH-II ameliorates experimental colitis by reducing not only the number of activated T cells but also the frequency of macrophages, neutrophils, and NK/NKT cell, as well as inflammatory miRNAs and cytokine at effector sites in the colon. These studies demonstrate for the first time that FAAH-II inhibitor may suppress colitis through regulation of pro-inflammatory miRNAs expression.

High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known about how the lipid composition of a HFD can influence prooncogenic processes. We examined the effects of three HFDs differing in the percentage of total calories from saturated fat (SF) (6, 12, and 24% of total caloric intake), but identical in total fat (40%), and a commercially available Western diet (26 and 41% saturated and total fat, respectively) on colon cancer development using the azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model. A second dose-response experiment was performed using diets supplemented with the saturated-fatty-acid (SFA)-rich coconut oil. In experiment 1, we found an inverse association between SF content and tumor burden. Furthermore, increased SF content was associated with reduced inflammation, increased apoptosis, and decreased proliferation. The second dose-response experiment was performed to test whether this effect may be attributed to the SF content of the diets. Consistent with the initial experiment, we found that high SF content was protective, at least in male mice; there was a decrease in mortality in mice consuming the highest concentration of SFAs. To explore a potential mechanism for these findings, we examined colonic mucin 2 (Muc2) protein content and found that the HFDs with the highest SF content had the greatest concentration of Muc2. Our data suggest that high dietary SF is protective in the AOM/DSS model of colon cancer, which may be due, at least in part, to the ability of SF to maintain intestinal barrier integrity through increased colonic Muc2.

Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male Apc Min/+, Apc Min/+/MCP-1−/− or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, β-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% ( P < 0.05). This was consistent with an increase in apoptotic cells ( P < 0.05), but there was no change detected in proliferation or β-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue ( P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL-13, CD206, TGF-β, and CCL17) ( P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells ( P < 0.05). In addition, MCP-1−/− offset the increased mRNA expression of IL-1β and IL-6 in intestinal tissue and IL-1β and TNF-α in polyp tissue ( P < 0.05), and prevented the decrease in SOCS1 expression ( P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer.

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. While the link between inflammation and colon cancer is well established, the temporal sequence of the inflammatory response in relation to tumorigenesis has not been characterized. We examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc(Min/+) mouse. Apc(Min/+) mice and wildtype mice were sacrificed at one of 4 time-points: 8, 12, 16, and 20 weeks of age. Intestinal tissue was analyzed for polyp burden (sections 1, 4 and 5) and mRNA expression and protein concentration of MCP-1, IL-1β, IL-6 and TNF-α (sections 2 and 3). The results show that polyp burden was increased at 12, 16 and 20 weeks compared to 8 weeks (P

Numerous in vitro studies argue for quercetin's chemopreventive potential in colon cancer; however, experimental studies in rodents are limited. Macrophages play a role in tumorigenesis, but the effects of quercetin on macrophage infiltration in colon cancer is unknown. We examined the effects of quercetin on intestinal polyp multiplicity and macrophage number in Apc(Min/+) mice. Apc(Min/+) mice were assigned to placebo or quercetin (n = 8/group) groups. Mice were given a placebo or quercetin (0.02%) diet from 4-20 wk of age, after which intestines were analyzed for polyp number and size in the small intestine (Sections 1-4) and colon (Section 5) and for macrophage number in the small intestine (Sections 1 and 3). Spleen weight was determined as a marker of systemic inflammation. Quercetin decreased total intestinal polyps by 67% (P0.05). Specifically, quercetin reduced intestinal polyps in categories2 mm (69%) and 1-2 mm (79%; P0.05), and in Sections 2 (75%), 3 (80%), and 4 (79%; P0.05). Quercetin also decreased macrophage number in Sections 1 (57%) and 3 (81%), and spleen weight (P0.05). These data suggest that quercetin can reduce polyp number and size distribution in the Apc(Min/+) mouse and that these effects may be related to a reduction in macrophage infiltration.

Curcumin's benefits on tumorigenesis are thought to be mediated by its antiinflammatory activity; however, these effects have not been well characterized in a mouse model of colon cancer. We examined the effects of curcumin on intestinal inflammation in the ApcMin/+ mouse. ApcMin/+ mice were given a placebo or curcumin (2%) diet from 4 to 18 weeks of age (n = 10/group). C57BL/6 mice were used as a wild-type control (n = 10/group). Intestines were analyzed for polyp burden (sections 1, 4, and 5) and for mRNA expression, and concentration of interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and chemokine ligand 2 (CCL2) (sections 2 and 3). Plasma was collected for concentration of CCL2. Curcumin decreased total intestinal polyps by 75% (P 2 mm (65%), 1–2 mm (72%)

To examine the recent scientific literature on the immune modulating effects of β-glucans and subsequent benefits on infection and cancer.β-Glucans have been investigated for their ability to protect against infection and cancer and more recently for their therapeutic potential when combined with cancer therapy. Their immune modulating effects are attributed to the ability to bind to pattern recognition receptors including complement receptor 3, scavenger receptors, lactosylceramide, and dectin-1 that results in activation of different aspects of the immune response depending on the cell types and species involved although there is some controversy about the relative importance of each of these receptors. Most of the available evidence comes from preclinical data and human studies are just now beginning to appear in the literature, therefore firm conclusions on its clinical importance cannot yet be made. Perhaps the most promising evidence to date in human trials has come from recent studies on a benefit of β-glucan on quality of life and survival when given in combination with cancer treatment. We identify the need for future studies that compare purified forms of β-glucans from different sources to further the understanding of the mechanisms of action and aid in the development of clinical studies.β-Glucans appear to be effective at enhancing immune function and reducing susceptibility to infection and cancer. A better understanding of the mechanisms of β-glucan recognition and subsequent immune activation is necessary for the design of effective treatment approaches in future clinical trials.

Oat β-glucan can counteract the exercise-induced increased risk for upper respiratory tract infection (URTI) in mice, which is at least partly mediated by its effects on lung macrophages. Substantial evidence in humans indicates that carbohydrate-containing sports drinks can offset the decreased immune function associated with stressful exercise. However, no studies in animals or humans have directly examined their effects on URTI using a controlled virus-challenge model. We examined the effects of sucrose feedings alone and in combination with oat β-glucan on susceptibility to infection and on macrophage antiviral resistance in mice following stressful exercise. These effects were also examined in rested, nonimmunocompromised control mice. Mice were assigned to one of four groups: H2O (water), sucrose (S), oat β-glucan (OβG), and sucrose + oat β-glucan (S+OβG). OβG and S treatments consisted of a solution of 50% OβG and 6% sucrose, respectively, and were administered in drinking water for 10 consecutive days. Exercise consisted of a treadmill run to fatigue performed on three consecutive days. Mice were then intranasally inoculated with a standardized dose of herpes simplex virus 1 (HSV-1) and monitored for morbidity and mortality for 21 days. Additional mice were used to determine macrophage antiviral resistance. In the exercise experiment, S, OβG, and S+OβG all reduced morbidity ( P < 0.05), while only S+OβG reduced mortality ( P < 0.05). Macrophage antiviral resistance was also increased in S, OβG, and S+OβG treatments ( P < 0.05). In resting controls, S and S+OβG reduced morbidity and mortality ( P < 0.05) and showed a trend toward increased macrophage antiviral resistance. There was no significant additive effect of S and OβG in either control or exercised animals. These data extend our previous work on the benefits of oat β-glucan to show that sucrose feedings have similar effects on susceptibility to respiratory infection and macrophage antiviral resistance in both resting controls and following exercise stress.

Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155−/− mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-β/SMAD pathway in miR-155−/− mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer.

Crohn’s disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P < 0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1β and TNF-α in IBD patients when compared to healthy donors (P < 0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.

We propose the hypothesis that the benefits of exercise on inflammation in cancer are a result of a direct effect on inflammatory cytokines, including interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein 1, that are critical for cancer growth as well as a bystander effect of the established relationship between exercise and cancer.

The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor—κB) signaling.

Noncoding RNAs are emerging as regulators of inflammatory and metabolic processes. There is evidence to suggest that miRNA155 (miR155) may be linked to inflammation and processes associated with adipogenesis. We examined the impact of global miRNA‐155 deletion (miR155 −/− ) on the development of high‐fat diet (HFD)‐induced obesity. We hypothesized that loss of miR155 would decrease adipose tissue inflammation and improve the metabolic profile following HFD feedings. Beginning at 4–5 weeks of age, male miR155 −/− and wild‐type (WT) mice ( n = 13–14) on a C57BL/6 background were fed either a HFD or low‐fat diet for 20 weeks. Body weight was monitored throughout the study. Baseline and terminal body composition was assessed by DEXA analysis. Adipose tissue mRNA expression (RT‐qPCR) of macrophage markers (F4/80, CD11c, and CD206) and inflammatory mediators (MCP‐1 and TNF‐ α ) as well as adiponectin were measured along with activation of NF κ B‐p65 and JNK and PPAR‐ γ . Adipose tissue fibrosis was assessed by picrosirius red staining and western blot analysis of Collagen I, III, and VI. Glucose metabolism and insulin resistance were assessed by Homeostatic Model Assessment – Insulin Resistance (HOMA‐IR), and a glucose tolerance test. Compared to WT HFD mice, miR155 −/− HFD mice displayed similar body weights, yet reduced visceral adipose tissue accumulation. However, miR155 −/− HFD displayed exacerbated adipose tissue fibrosis and decreased PPAR‐ γ protein content. The loss of miR155 did not affect adipose tissue inflammation or glucose metabolism. In conclusion, miR155 deletion did not attenuate the development of the obese phenotype, but adipose tissue fibrosis was exacerbated, possibly through changes to adipogenic processes.

Inflammatory bowel disease (IBD), a chronic intestinal inflammatory condition that affects millions of people worldwide, results in high morbidity and exorbitant health-care costs. The critical features of both innate and adaptive immunity are to control inflammation and dysfunction in this equilibrium is believed to be the reason for the development of IBD. miR-155, a microRNA, is up-regulated in various inflammatory disease states, including IBD, and is a positive regulator of T-cell responses. To date, no reports have defined a function for miR-155 with regard to cellular responses in IBD. Using an acute experimental colitis model, we found that miR-155(-/-) mice, as compared to wild-type control mice, have decreased clinical scores, a reversal of colitis-associated pathogenesis, and reduced systemic and mucosal inflammatory cytokines. The increased frequency of CD4+ lymphocytes in the spleen and lamina propria with dextran sodium sulphate induction was decreased in miR-155(-/-) mice. Similarly, miR-155 deficiency abrogated the increased numbers of interferon-γ expressing CD4+ T cells typically observed in wild-type mice in this model. The frequency of systemic and mucosal T helper type 17-, CCR9-expressing CD4+ T cells was also reduced in miR-155(-/-) mice compared with control mice. These findings strongly support a role for miR-155 in facilitating pro-inflammatory cellular responses in this model of IBD. Loss of miR-155 also results in decreases in T helper type 1/type 17, CD11b+) and CD11c+ cells, which correlated with reduced clinical scores and severity of disease. miR-155 may serve as a potential therapeutic target for the treatment of IBD.